title: Redox-active quinones and ascorbate: an innovative cancer therapy that exploits the vulnerability of cancer cells to oxidative stress.
abstract: Cancer cells are particularly vulnerable to treatments impairing redox homeostasis. Reactive oxygen species (ROS) can indeed play an important role in the initiation and progression of cancer, and advanced stage tumors frequently exhibit high basal levels of ROS that stimulate cell proliferation and promote genetic instability. In addition, an inverse correlation between histological grade and antioxidant enzyme activities is frequently observed in human tumors, further supporting the existence of a redox dysregulation in cancer cells. This biochemical property can be exploited by using redox-modulating compounds, which represent an interesting approach to induce cancer cell death. Thus, we have developed a new strategy based on the use of pharmacologic concentrations of ascorbate and redox-active quinones. Ascorbate-driven quinone redox cycling leads to ROS formation and provoke an oxidative stress that preferentially kill cancer cells and spare healthy tissues. Cancer cell death occurs through necrosis and the underlying mechanism implies an energetic impairment (ATP depletion) that is likely due to glycolysis inhibition. Additional mechanisms that participate to cell death include calcium equilibrium impairment and oxidative cleavage of protein chaperone Hsp90. Given the low systemic toxicity of ascorbate and the impairment of crucial survival pathways when associated with redox-active quinones, these combinations could represent an original approach that could be combined to standard cancer therapy.
authors.affiliation: Toxicology and Cancer Biology Research Group, Louvain Drug Research Institute (LDRI), Université Catholique de Louvain, Brussels, Belgium. .
authors.forename: J
authors.initials: J
authors.lastname: Verrax
authors.forename: R
authors.initials: R
authors.lastname: Beck
authors.forename: N
authors.initials: N
authors.lastname: Dejeans
authors.forename: C
authors.initials: C
authors.lastname: Glorieux
authors.forename: B
authors.initials: B
authors.lastname: Sid
authors.forename: R Curi
authors.initials: RC
authors.lastname: Pedrosa
authors.forename: J
authors.initials: J
authors.lastname: Benites
authors.forename: D
authors.initials: D
authors.lastname: Vásquez
authors.forename: J A
authors.initials: JA
authors.lastname: Valderrama
authors.forename: P Buc
authors.initials: PB
authors.lastname: Calderon
mesh_terms: D000970:Antineoplastic Agents; D000975:Antioxidants / Q000627:therapeutic use; D001205:Ascorbic Acid / Q000494:pharmacology* / Q000627:therapeutic use; D006801:Humans; D009369:Neoplasms / Q000188:drug therapy* / Q000378:metabolism; D018384:Oxidative Stress / Q000187:drug effects*; D011809:Quinones / Q000494:pharmacology* / Q000627:therapeutic use
chemical_list: D000970:Antineoplastic Agents; D000975:Antioxidants; D011809:Quinones; D001205:Ascorbic Acid